Insects are the primary vectors for many deadly diseases. Mosquitoes and other blood-feeding insects are attracted to their human hosts via volatile olfactory cues. Consequently, the transmission of insect-borne diseases could be effectively controlled through strategies that target insect odorant receptors, disrupt the initial detection of human volatiles and prevent mosquitoes and other vectors from locating their human hosts. Insect odorant receptors are thought to form a novel class of heteromeric ion channels comprised of two distinct subunits-a highly divergent odorant receptor (OR) subunit that confers odorant specificity and a common Orco subunit, that is virtually invariant amongst diverse insect species, reflecting an absolutely essential role in olfactory transduction. Unfortunately as these receptors lack any structural homologs, many of their most fundamental structural and functional properties remain elusive, precluding sufficient mechanistic understanding to guide drug design. The objective of this proposal is to bring much-needed molecular insight to insect odorant receptors. We plan to perform X-ray crystallographic studies on Orco, alone and in complex with previously identified small-molecule agonists and antagonists, as a strategy to reveal the structural and mechanistic basis for modulation in this critical olfactory channel. In parallel, we have devised functional assays that allow us to probe the structural basis for Orco function and pharmacology, both in vitro using mutational analysis, and in vivo. Together, these studies will provide atomic insight into the mechanism by which the Orco channel functions and can be modulated, laying the foundation for the rational design of small molecule repellents that disrupt odor detection and host-seeking behavior in insect vectors of human disease.